Oxygen Sensing and Ferroptosis in Cancer

Cell death plays important roles in normal biology and disease. Among various modalities of cell death, ferroptosis is a form of cell death driven by iron-dependent (thus the name) phospholipid peroxidation. Mounting evidence indicates that ferroptosis is highly relevant to cancer and contributes to the anticancer function of multiple tumor suppressors. Interestingly, altered metabolism, while providing growth advantage, often makes cancer cells more sensitive to ferroptosis. Further, we and others discovered that various signal transduction pathways impact ferroptosis through their role in modulating cellular metabolism. As these signaling pathways are frequently mutated in human cancer, these studies have provided strong evidence supporting that ferroptosis induction, either as a single-agent therapy or in combination with other regimens, might be an effective therapeutic approach for the treatment of cancers harboring specific oncogenic mutations. Hypoxia exerts profound effect on both normal biology and cancer via altering, among others, cellular redox and metabolic status. The oxidative and metabolic nature of ferroptosis prompted us to investigate how hypoxia might regulate ferroptosis. Our preliminary study revealed that prolonged hypoxia inhibits ferroptosis almost completely, and intriguingly, this effect is independent of the canonical oxygen-sensing mechanism mediated by prolyl hydroxylases (PHDs), the von Hippel–Lindau protein (VHL), and hypoxia inducing factors (HIFs). Instead, we found that histone demethylase KDM6A, which is a tumor suppressor frequently mutated in various cancers and which requires oxygen for its enzymatic activity, plays a central role in mediating the regulation of ferroptosis by hypoxia, i.e., KDM6A can function as a direct oxygen sensor for ferroptosis regulation. As sustained tumor hypoxia and loss-of-function mutation of KDM6A often exacerbate malignancy, we hypothesize that ferroptosis resistance is a contributor to the enhanced malignancy of KDM6A-defective cancer. In this proposal, we will investigate this central hypothesis by determining the mechanisms by which prolonged hypoxia and KDM6A regulate ferroptosis and the implication of the learned mechanisms in cancer progression and therapy. The innovative research proposed in this application will lead to important basic understanding of oxygen sensing and ferroptosis in cancer and shed light on novel strategy and biomarker identification for ferroptosis induction-based cancer therapy. Project Number: 1R01CA310056-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Xuejun Jiang | Institution: SLOAN-KETTERING INST CAN RESEARCH, NEW YORK, NY | Award Amount: $614,260 | Activity Code: R01 | Study Section: Cancer Cell Biology Study Section[CCB] View on NIH RePORTER: https://reporter.nih.gov/project-details/11320242